rs213950

Variant names:

• chr7-117559479-G-A
• rs213950
• NM_000492.4:c.1408G>A

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 5P and 20B. PM1 PM5 PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000492.4(CFTR):​c.1408G>A​(p.Val470Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.439 in 1,597,726 control chromosomes in the GnomAD database, including 164,304 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V470G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.56 (26569 hom., cov: 31)
  • Exomes 𝑓: 0.43 (137735 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:21
• Conservation: PhyloP100: 2.57
• Publications: 255 publications found

Genes affected

CFTR (HGNC:1884): (CF transmembrane conductance regulator) This gene encodes a member of the ATP-binding cassette (ABC) transporter superfamily. The encoded protein functions as a chloride channel, making it unique among members of this protein family, and controls ion and water secretion and absorption in epithelial tissues. Channel activation is mediated by cycles of regulatory domain phosphorylation, ATP-binding by the nucleotide-binding domains, and ATP hydrolysis. Mutations in this gene cause cystic fibrosis, the most common lethal genetic disorder in populations of Northern European descent. The most frequently occurring mutation in cystic fibrosis, DeltaF508, results in impaired folding and trafficking of the encoded protein. Multiple pseudogenes have been identified in the human genome. [provided by RefSeq, Aug 2017]

CFTR-AS1 (HGNC:40144): (CFTR antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• PM1: In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 25 uncertain in NM_000492.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-117559480-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 3336635.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 197 curated pathogenic missense variants (we use a threshold of 10). The gene has 46 curated benign missense variants. Gene score misZ: -3.1397 (below the threshold of 3.09). Trascript score misZ: -1.0868 (below the threshold of 3.09). GenCC associations: The gene is linked to hereditary chronic pancreatitis, cystic fibrosis, congenital bilateral absence of vas deferens.
• BP4: Computational evidence support a benign effect (MetaRNN=9.284489E-7).
• BP6: Variant 7-117559479-G-A is Benign according to our data. Variant chr7-117559479-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 7130.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.854 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000492.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	NM_000492.4	MANE Select	c.1408G>A	p.Val470Met	missense	Exon 11 of 27	NP_000483.3
	CFTR-AS1	NR_149084.1		n.221+1254C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	ENST00000003084.11	TSL:1 MANE Select	c.1408G>A	p.Val470Met	missense	Exon 11 of 27	ENSP00000003084.6	P13569-1
	CFTR	ENST00000699602.1		c.1408G>A	p.Val470Met	missense	Exon 11 of 27	ENSP00000514471.1	A0A8V8TNH2
	CFTR	ENST00000889206.1		c.1408G>A	p.Val470Met	missense	Exon 11 of 26	ENSP00000559265.1

Frequencies

GnomAD3 genomes AF: 0.557 AC: 84573 AN: 151846 Hom.: 26503 Cov.: 31

Gnomad AFR AF: 0.861

Gnomad AMI AF: 0.316

Gnomad AMR AF: 0.518

Gnomad ASJ AF: 0.277

Gnomad EAS AF: 0.419

Gnomad SAS AF: 0.488

Gnomad FIN AF: 0.562

Gnomad MID AF: 0.399

Gnomad NFE AF: 0.415

Gnomad OTH AF: 0.507

GnomAD2 exomes AF: 0.475 AC: 119239 AN: 251166 AF XY: 0.464

Gnomad AFR exome AF: 0.871

Gnomad AMR exome AF: 0.528

Gnomad ASJ exome AF: 0.284

Gnomad EAS exome AF: 0.420

Gnomad FIN exome AF: 0.549

Gnomad NFE exome AF: 0.413

Gnomad OTH exome AF: 0.452

GnomAD4 exome AF: 0.427 AC: 616894 AN: 1445762 Hom.: 137735 Cov.: 30 AF XY: 0.427 AC XY: 307171 AN XY: 720158

African (AFR) AF: 0.881 AC: 29129 AN: 33072

American (AMR) AF: 0.521 AC: 23304 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.283 AC: 7363 AN: 26044

East Asian (EAS) AF: 0.406 AC: 16061 AN: 39550

South Asian (SAS) AF: 0.475 AC: 40761 AN: 85900

European-Finnish (FIN) AF: 0.547 AC: 29100 AN: 53222

Middle Eastern (MID) AF: 0.387 AC: 2220 AN: 5736

European-Non Finnish (NFE) AF: 0.403 AC: 442722 AN: 1097698

Other (OTH) AF: 0.438 AC: 26234 AN: 59844

GnomAD4 genome AF: 0.557 AC: 84699 AN: 151964 Hom.: 26569 Cov.: 31 AF XY: 0.561 AC XY: 41636 AN XY: 74256

African (AFR) AF: 0.861 AC: 35759 AN: 41512

American (AMR) AF: 0.518 AC: 7908 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.277 AC: 962 AN: 3468

East Asian (EAS) AF: 0.419 AC: 2161 AN: 5158

South Asian (SAS) AF: 0.488 AC: 2352 AN: 4820

European-Finnish (FIN) AF: 0.562 AC: 5917 AN: 10526

Middle Eastern (MID) AF: 0.378 AC: 111 AN: 294

European-Non Finnish (NFE) AF: 0.415 AC: 28165 AN: 67914

Other (OTH) AF: 0.510 AC: 1076 AN: 2110

Alfa AF: 0.444 Hom.: 71118

Bravo AF: 0.564

TwinsUK AF: 0.403 AC: 1493

ALSPAC AF: 0.391 AC: 1507

ESP6500AA AF: 0.850 AC: 3747

ESP6500EA AF: 0.468 AC: 4026

ExAC AF: 0.483 AC: 58619

Asia WGS AF: 0.527 AC: 1834 AN: 3478

EpiCase AF: 0.394

EpiControl AF: 0.390

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	7	Cystic fibrosis (7)
-	-	4	CFTR-related disorder (4)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.049
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	14
DANN	Benign	0.72
DEOGEN2	Uncertain	0.53	D
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.68	T
MetaRNN	Benign	9.3e-7	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.14	N
PhyloP100		2.6
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	0.48	N
REVEL	Uncertain	0.46
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.069
MPC		0.0040
ClinPred		0.0091	T
GERP RS		3.0
Varity_R		0.23
gMVP		0.80
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs213950; hg19: chr7-117199533; COSMIC: COSV50040905; COSMIC: COSV50040905;